The Pathophysiology and Treatment of Children with Severe Irritability

儿童严重烦躁的病理生理学和治疗

• 批准号: 10012696
• 负责人: Ellen Leibenluft
• 金额: $ 314.89万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10012696
• 关键词: Adolescent; Adverse event; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Base of the Brain; Behavior; Behavioral; Brain; Child; Childhood; Chronic; Citalopram; Clinical; Clinical Trials; Cognitive; Corpus striatum structure; DSM-V; Data; Development; Diagnosis; Dimensions; Disease; Double-blind trial; Enrollment; Evidence based treatment; Exhibits; Feedback; Fostering; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hospitalization; Human; Image; Impairment; Individual; Knowledge; Lead; Learning; Literature; Machine Learning; Manuscripts; Mediating; Methodology; Modeling; Moods; National Institute of Mental Health; Operant Conditioning; Participant; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Population; Process; Protocols documentation; Public Health; Publishing; Research; Research Domain Criteria; Rest; Rewards; Sampling; Symptoms; Techniques; Testing; Time; Unipolar Depression; Variant; Work; Youth; analytical method; anxious; atypical antipsychotic; brain dysfunction; childhood anxiety; childhood bipolar disorder; cognitive control; cognitive task; comparison group; design; dysphoria; emotion regulation; environmental change; flexibility; heuristics; improved; inhibitor/antagonist; neuroimaging; novel; precision medicine; prevent; psychiatric symptom; recruit; relating to nervous system; response; reuptake; reward circuitry; severe mood dysregulation; side effect; standardize measure; translational approach; translational model; trial design

Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined severe mood dysregulation (SMD) to capture youth with severe irritability, as well as hyperarousal. SMD formed the basis for the new diagnosis of mood dysregulation disorder with dysphoria (DMDD)in DSM-5. Since the inception of this project (ZIA MH002786-17), approximately 450 highly irritable (i.e., those with SMD, DMDD, or sub-threshold DMDD) have enrolled into the project, along with more than 125 youth with ADHD. (Many DMDD patients have ADHD, and youth with ADHD tend to have less irritability than those with DMDD but more than healthy youth; hence they are an appropriate comparison group.) Approximately 50 new patients were recruited this year. Youth with DMDD suffer severe impairment, in terms of medications received, hospitalizations, and standardized measures of function. Irritability is one of the most common psychiatric symptoms in children, but there has been little brain-based research on it, and there are few evidence-based treatments. Recently, we published several major reviews and theoretical articles articulating a testable, heuristic, translational model of irritability to guide future research. The model posits that core deficits in pediatric irritability include aberrant responses to frustration and aberrant approach responses to threat. Aberrant responses to frustration implicate reward learning circuitry dysfunction e.g., deficits instrumental learning deficits that prevent adaptation to changing environmental contingencies, or exaggerated prediction error responses to the omission of an expected reward. In addition, evidence suggests that cognitive control deficits (specifically, deficient inhibitory control) may contribute to maladaptive behavior in response to either frustration or threat. Irritability is well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). We characterize irritability as a continuous variable, in DMDD and other groups, including youth with anxiety disorders or ADHD. We use frustrating tasks during neuroimaging, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. In a manuscript published this year, we found that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. This finding is more prominent in children than adolescents. Since prefrontal engagement is important in emotion regulation, this may indicate that prefrontal emotion regulation mechanisms are less efficient in irritable vs. non-irritable youth. Alternatively, in irritable youth, increased prefrontal engagement may be required after frustration to down-regulate exaggerated subcortical limbic responses e.g., in the striatum. These effects of irritability are present even when ADHD and anxiety are taken into account. In work published in 2018, we demonstrated associations between irritability and brain function when youth with DMDD, anxiety, or healthy subjects completed a threat-attention task. Because our translational model posits that both threat and reward (i.e., frustration) circuitry are implicated in irritability, we will next directly compare function in two brain circuits and the associations each have with irritability. Since youth with irritability have heterogeneous clinical presentations, precision medicine approaches would be fostered by testing whether irritable youth can be sub-grouped by dysfunction in threat vs. reward circuitry. We use previously acquired fMRI data from subjects who completed both the threat- and frustration-processing paradigms to develop and pilot new analytic methods and test these questions. We are also gathering data from a new, large sample of DMDD, anxious and ADHD subjects using the same two paradigms, to test these questions. In addition to the attention shifting frustration task described above, we have piloted two additional frustration tasks. The second frustration task differs from the first in the timing of frustration (short blocks of frustration, interspersed randomly with non-frustrating blocks, vs. a long block of non-frustration followed by a long bout of frustration) and in the cognitive task (attention orienting vs. cognitive flexibility). This second task allows us to test whether, across different task timing and cognitive tasks, increased irritability is associated with increased prefrontal engagement after frustration. We are now using new machine learning techniques to analyze data from 80 healthy youth or those with DMDD, anxiety, or ADHD. We have adapted the second task so that, while it maintains its unique methodological features, its design is sufficiently comparable to the frustrating attentional task to allow direct statistical comparisons. This will allow us to identify frustration-related findings that are robust to methodological variation, while also isolating the impact of different approaches on the findings. Such data will thus be informative not only about the brain mechanisms associated with irritability, but also future directions of research. In addition, both frustration tasks are accompanied by resting state data acquired pre- and post- the frustration task, so we can identify how frustration, elicited by two different techniques, impacts on intrinsic brain connectivity. Our third frustration task allows us to determine if irritability is associated with instrumental learning deficits at baseline and after frustration. Instrumental learning is the process by which people learn which of their behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. We successfully piloted this task outside the scanner and are now acquiring imaging data. A long-standing and important question in the literature is the extent to which deficits in cognitive control, particularly inhibitory control, play in the pathophysiology of temper outbursts. Given the significant overlap between ADHD symptoms and irritability, an important goal of this study is to differentiate the associations of each of these with deficient inhibitory ability. We are testing youth with DMDD, ADHD, and anxiety on an extensive battery of inhibitory control tasks. The use of this extensive battery allows us to derive latent variables which are more stable than those derived from an individual study and are thus more likely to yield replicable results. As noted above, a major focus of our work is treatment. We completed our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability. In a sample of 49 youth, we demonstrated that indeed, stimulant plus citalopram is more effective in reducing irritability than is stimulant plus placebo. These data have recently been published. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which is used frequently in youth with severe irritability. Therefore, this work has considerable public health importance. New treatment approaches are now being developed and tested under 15-M-0182 (NCT02531893); PI: Brotman.

考虑到对患有慢性，严重烦躁的儿童进行适当诊断的担忧，我们确定了严重的情绪失调（SMD），以捕获患有严重烦躁和高音的青年。 SMD构成了DSM-5中新诊断对情绪失调障碍（DMDD）的新诊断。自从该项目（Zia MH002786-17）成立以来，大约450个非常烦躁的（即，具有SMD，DMDD或阈值dmdd的人）已经招募了该项目，以及125多名ADHD的年轻人。 （许多DMDD患者患有多动症，患有多动症的年轻人往往比患有DMDD但健康的年轻人更易怒；因此，他们是一个合适的比较组。）今年大约有50名新患者被招募。 DMDD的年轻人在接受的药物，住院和标准化功能指标方面遭受严重损害。烦恼是儿童中最常见的精神病症状之一，但基于大脑的研究很少，几乎没有循证治疗。最近，我们发表了几篇主要的评论和理论文章，阐明了一种可检验的，启发式的转化模型，以指导未来的研究。 该模型认为，小儿烦躁的核心缺陷包括对挫败感的异常反应和对威胁的异常方法的反应。对挫败感的异常反应暗示奖励学习电路功能障碍，例如，赤字会削弱工具性学习缺陷，以防止适应不断变化的环境意外情况，或夸张的预测错误响应对省略预期奖励的错误响应。此外，有证据表明，认知控制缺陷（特别是缺乏抑制性控制）可能会导致适应不良的行为，以应对挫败感或威胁。 烦恼非常适合研究领域标准（RDOC）的转换，翻译方法。在DMDD和其他群体中，包括患有焦虑症或多动症的青年，我们将烦躁的变量描述为连续变量。在神经影像学期间，我们使用令人沮丧的任务，因为烦躁的标志是难以容忍挫败感。以前，我们在令人沮丧的注意力任务中表现出了易怒和不可训练的青年之间的行为和神经差异。我们改善了该范式，并从大约200名患有DMDD，ADHD和/或焦虑症的年轻人以及健康的青年中获得了fMRI数据。在今年出版的手稿中，我们发现，当年轻人在收到令人沮丧的反馈后尝试将注意力置于注意力方面时，烦躁与前额叶和纹状体的参与有关。在儿童中，这一发现比青少年更为突出。由于前额叶参与在情绪调节中很重要，因此这可能表明前额叶情绪调节机制在易怒中效率较低，与非摩擦年轻人的效率较低。另外，在挫败感后，可能需要增加前额叶参与度，以下调夸张的皮层边缘反应，例如在纹状体中。即使考虑到多动症和焦虑，也会存在这些烦躁的影响。 在2018年出版的工作中，当患有DMDD，焦虑或健康受试者的年轻人完成威胁注意任务时，我们证明了烦躁和大脑功能之间的关联。因为我们的翻译模型认为威胁和奖励（即挫败感）电路涉及易怒，所以我们接下来将直接比较两个大脑回路中的功能，并且每个关联都具有易怒。由于易怒的年轻人具有异质的临床表现，因此可以通过测试威胁与奖励电路中的功能障碍来测试易怒的青年是否可以通过功能障碍来促进精确医学方法。我们使用以前获得的fMRI数据来自完成威胁和沮丧处理范式的受试者，以开发和试行新的分析方法并测试这些问题。我们还使用相同的两个范式从新的大量DMDD，焦虑和多动症主题中收集数据，以测试这些问题。 除了上面描述的注意力转移挫败感的任务外，我们还试行了另外的两个挫败感。第二个挫败感任务与挫败感的时间（挫折的短块，散布在非填充的障碍物中，与不折磨的长块随机散布在一起）和认知任务（注意力方向与认知灵活性）中的第二个挫折任务不同。这第二个任务使我们能够测试在不同的任务时间和认知任务中，烦躁的增加是否与沮丧后的前额叶参与度增加有关。现在，我们正在使用新的机器学习技术来分析80名健康青年或DMDD，焦虑或多动症患者的数据。我们已经改编了第二个任务，以便尽管它保持其独特的方法论特征，但其设计与令人沮丧的注意力任务相当，可以直接统计比较。 这将使我们能够识别与挫败感相关的发现，这些发现对方法论上的差异很强，同时也隔离了不同方法对发现的影响。因此，这些数据不仅会使与烦躁的大脑机制有关，而且还会吸引未来的研究方向。 此外，这两个挫折任务都伴随着静止状态数据获得了挫败感的任务，因此我们可以确定两种不同技术引起的挫败感如何影响内在的大脑连接性。 我们的第三项挫败感使我们能够确定烦躁的能力是否与基线和挫败感后的器乐学习缺陷有关。乐器学习是人们学习哪些行为的过程。这种学习的缺陷可能导致易怒的青年挫败感。我们成功地在扫描仪之外试行了此任务，现在正在获取成像数据。 文献中的一个长期和重要的问题是，认知控制中的缺陷，尤其是抑制性控制的程度，在脾脏爆发的病理生理学中发挥作用。 鉴于多动症症状和易怒性之间存在显着的重叠，这项研究的重要目标是将每一种关联与不足的抑制能力区分开。我们正在用DMDD，ADHD和焦虑症的年轻人测试大量抑制控制任务。这种广泛的电池的使用使我们能够得出比从个人研究中得出的更稳定的潜在变量，因此更有可能产生可复制的结果。 如上所述，我们工作的主要重点是治疗。我们完成了双盲试验，旨在确定西妥位酰胺（血清素能再摄取抑制剂（SRI）抗抑郁药，可有效治疗小儿焦虑）加上刺激剂，而不是安慰剂加刺激剂在治疗严重易怒的治疗方面是否更有效。在49名青年的样本中，我们证明，确实，刺激性加上西妥位蛋白己在降低易怒性方面比刺激性加上安慰剂更有效。这些数据最近已发布。刺激性和SRI治疗的副作用往往比非典型抗精神病药物的副作用少，这在严重烦躁的年轻人中经常使用。因此，这项工作具有相当大的公共健康重要性。现在正在开发和测试新的治疗方法，并在15-m-0182（NCT02531893）下进行测试； PI：Brotman。